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Macrophage SCAP Contributes to Metaflammation and Lean NAFLD by Activating STING–NF-κB Signaling Pathway

Huang, Xinyu, Yao, Yingcheng, Hou, Xiaoli, Wei, Li, Rao, Yuhan, Su, Yu, Zheng, Guo, Ruan, Xiong Z., Li, Danyang, Chen, Yaxi·2022·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2022.03.006PMC PMC9117819
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Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 Nonobese metabolic syndrome induced by PD feeding features lean NAFLD. (A) Body weight gain curves of mice fed 12-week NCD and PD (n = 6). (B) Levels of total TG, TC, HDL cholesterol, and LDL in plasma (n = 6). Intraperitoneal GTT levels (C) and intraperitoneal ITT levels (D) in NCD- and PD-fed mice (n = 6). (E) Representative pictures and H&E staining of eWAT, and the histogram represents eWAT/body weight (n = 6). (F) Representative pictures and H&E staining of liver tissues, and the histogram represents liver/body weight (n = 6). (G) Representative images of Oil Red O staining in liver tissues (n = 6). (H) Levels of intrahepatic TC and TG (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs and two-way analysis of variance in body weight, GTT, and ITT curves).
Figure 1 Nonobese metabolic syndrome induced by PD feeding features lean NAFLD. (A) Body weight gain curves of mice fed 12-week NCD and PD (n = 6). (B) Levels of total TG, TC, HDL cholesterol, and LDL in plasma (n = 6). Intraperitoneal GTT levels (C) and intraperitoneal ITT levels (D) in NCD- and PD-fed mice (n = 6). (E) Representative pictures and H&E staining of eWAT, and the histogram represents eWAT/body weight (n = 6). (F) Representative pictures and H&E staining of liver tissues, and the histogram represents liver/body weight (n = 6). (G) Representative images of Oil Red O staining in liver tissues (n = 6). (H) Levels of intrahepatic TC and TG (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs and two-way analysis of variance in body weight, GTT, and ITT curves).CC BY-NC-ND · PubMed Central
Figure 2 Lean NAFLD induced by PD feeding displays evident inflammation in eWAT and liver. (A) Immunohistochemical staining of F4/80+ cells in eWAT (n = 6). (B) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in eWAT (n = 6). (C) Immunohistochemical staining of F4/80+ cells in liver tissues (n = 6). (D) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). Enzyme-linked immunosorbent assay analysis of protein expression of IL1β, IL6, and TNF-α in eWAT (E) and in liver tissues (F) (n = 6). (G) Protein levels of TNF-α, IL1β, and IL6 in liver tissues (n = 6). (H) Levels of ALT and aspartate aminotransferase in plasma (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 2 Lean NAFLD induced by PD feeding displays evident inflammation in eWAT and liver. (A) Immunohistochemical staining of F4/80+ cells in eWAT (n = 6). (B) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in eWAT (n = 6). (C) Immunohistochemical staining of F4/80+ cells in liver tissues (n = 6). (D) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). Enzyme-linked immunosorbent assay analysis of protein expression of IL1β, IL6, and TNF-α in eWAT (E) and in liver tissues (F) (n = 6). (G) Protein levels of TNF-α, IL1β, and IL6 in liver tissues (n = 6). (H) Levels of ALT and aspartate aminotransferase in plasma (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 3 Lean NAFLD induced by PD feeding displays evident lipid metabolism disorders in eWAT and liver. Relative mRNA levels of lipolysis (A), lipid synthesis (B), and lipid uptake (C) in eWAT (n = 6). Relative mRNA levels of lipolysis (D), lipid synthesis (E), and lipid uptake (F) in liver tissues (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 3 Lean NAFLD induced by PD feeding displays evident lipid metabolism disorders in eWAT and liver. Relative mRNA levels of lipolysis (A), lipid synthesis (B), and lipid uptake (C) in eWAT (n = 6). Relative mRNA levels of lipolysis (D), lipid synthesis (E), and lipid uptake (F) in liver tissues (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 4 Macrophage SCAP expression is abnormally increased in eWAT and liver tissues of PD-fed mice. (A) Immunofluorescence staining of SCAP and F4/80 in eWAT and liver tissues (n = 3). (B) Flow cytometry was used to analyze expression of SCAP in F4/80+CD11c+ macrophages of eWAT (n = 3). (C) Flow cytometry was used to analyze expression of SCAP in F4/80+CD11b+ macrophages of liver tissues (n = 3). (D) Mice with macrophage/monocyte-specific deletion of SCAP (SCAPΔMϕ mice) were generated by crossing SCAPfl/fl mice with LysM Cre mice. (E) Genotyping SCAP knockout mice by PCR showed different genotypes: SCAP+/+, SCAP+/−, SCAP−/−. (F) Relative mRNA levels of SCAP in bone marrow-derived macrophage cells. (G) Schematic outline of experimental approaches and analyses. Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 4 Macrophage SCAP expression is abnormally increased in eWAT and liver tissues of PD-fed mice. (A) Immunofluorescence staining of SCAP and F4/80 in eWAT and liver tissues (n = 3). (B) Flow cytometry was used to analyze expression of SCAP in F4/80+CD11c+ macrophages of eWAT (n = 3). (C) Flow cytometry was used to analyze expression of SCAP in F4/80+CD11b+ macrophages of liver tissues (n = 3). (D) Mice with macrophage/monocyte-specific deletion of SCAP (SCAPΔMϕ mice) were generated by crossing SCAPfl/fl mice with LysM Cre mice. (E) Genotyping SCAP knockout mice by PCR showed different genotypes: SCAP+/+, SCAP+/−, SCAP−/−. (F) Relative mRNA levels of SCAP in bone marrow-derived macrophage cells. (G) Schematic outline of experimental approaches and analyses. Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 5 Macrophage SCAP deletion does not alter eWAT and liver phenotype in NCD-fed mice. (A) Representative pictures and H&E staining of eWAT, and the histogram represents eWAT/body weight (n = 6). (B) Representative pictures and H&E staining of liver tissues, and the histogram represents liver/body weight (n = 6). (C) Immunohistochemical staining of F4/80+ cells in eWAT (n = 6). (D) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in eWAT (n = 6). (E) Immunohistochemical staining of F4/80+ cells in liver tissues (n = 6). (F) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). (G) Representative images of Oil Red O staining in liver tissues (n = 6). (H) Levels of intrahepatic TC and TG (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 5 Macrophage SCAP deletion does not alter eWAT and liver phenotype in NCD-fed mice. (A) Representative pictures and H&E staining of eWAT, and the histogram represents eWAT/body weight (n = 6). (B) Representative pictures and H&E staining of liver tissues, and the histogram represents liver/body weight (n = 6). (C) Immunohistochemical staining of F4/80+ cells in eWAT (n = 6). (D) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in eWAT (n = 6). (E) Immunohistochemical staining of F4/80+ cells in liver tissues (n = 6). (F) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). (G) Representative images of Oil Red O staining in liver tissues (n = 6). (H) Levels of intrahepatic TC and TG (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 6 Macrophage SCAP deletion improves metabolic syndrome and lean NAFLD in PD-fed mice. (A) Body weight gain curves of SCAPfl/fl and SCAPΔMϕ mice fed 12 weeks of PD (n = 6). (B) Levels of TC, HDL, and LDL in plasma (n = 6). GTT levels (C) and ITT levels (D) in SCAPΔMϕ and SCAPfl/fl mice (n = 6). (E) Representative pictures and H&E staining of eWAT, and the histogram represents eWAT/body weight (n = 6). (F) Representative pictures and H&E staining of liver tissues, and the histogram represents liver/body weight (n = 6). (G) Representative images of Oil Red O staining in liver tissues (n = 6). (H) Levels of TG in plasma and intrahepatic TG levels (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs and two-way analysis of variance in body weight, GTT, and ITT curves).
Figure 6 Macrophage SCAP deletion improves metabolic syndrome and lean NAFLD in PD-fed mice. (A) Body weight gain curves of SCAPfl/fl and SCAPΔMϕ mice fed 12 weeks of PD (n = 6). (B) Levels of TC, HDL, and LDL in plasma (n = 6). GTT levels (C) and ITT levels (D) in SCAPΔMϕ and SCAPfl/fl mice (n = 6). (E) Representative pictures and H&E staining of eWAT, and the histogram represents eWAT/body weight (n = 6). (F) Representative pictures and H&E staining of liver tissues, and the histogram represents liver/body weight (n = 6). (G) Representative images of Oil Red O staining in liver tissues (n = 6). (H) Levels of TG in plasma and intrahepatic TG levels (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs and two-way analysis of variance in body weight, GTT, and ITT curves).CC BY-NC-ND · PubMed Central
Figure 7 Macrophage SCAP deletion has ameliorative effects on metaflammation in eWAT and liver tissue of PD-fed mice. (A) Immunohistochemical staining of F4/80+ cells in eWAT (n = 6). (B) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in eWAT (n = 6). (C) Immunohistochemical staining of F4/80+ cells in liver tissues (n = 6). (D) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). Enzyme-linked immunosorbent assay analysis of protein expression of IL1β, IL6, and TNF-α in eWAT (E) and in liver tissues (F) (n = 6). (G) Protein levels of TNF-α, IL1β, and IL6 in liver tissues (n = 6). (H) Levels of ALT and aspartate aminotransferase in plasma (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 7 Macrophage SCAP deletion has ameliorative effects on metaflammation in eWAT and liver tissue of PD-fed mice. (A) Immunohistochemical staining of F4/80+ cells in eWAT (n = 6). (B) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in eWAT (n = 6). (C) Immunohistochemical staining of F4/80+ cells in liver tissues (n = 6). (D) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). Enzyme-linked immunosorbent assay analysis of protein expression of IL1β, IL6, and TNF-α in eWAT (E) and in liver tissues (F) (n = 6). (G) Protein levels of TNF-α, IL1β, and IL6 in liver tissues (n = 6). (H) Levels of ALT and aspartate aminotransferase in plasma (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 8 Macrophage SCAP deletion has ameliorative effects on lipid disorders in eWAT and liver tissue of PD-fed mice. Relative mRNA levels of lipolysis (A), lipid synthesis (B), and lipid uptake (C) in eWAT (n = 6). Relative mRNA levels of lipolysis (D), lipid synthesis (E), and lipid uptake (F) in liver tissues (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 8 Macrophage SCAP deletion has ameliorative effects on lipid disorders in eWAT and liver tissue of PD-fed mice. Relative mRNA levels of lipolysis (A), lipid synthesis (B), and lipid uptake (C) in eWAT (n = 6). Relative mRNA levels of lipolysis (D), lipid synthesis (E), and lipid uptake (F) in liver tissues (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 9 Expression levels of SCAP in macrophages also influences lipid homeostasis and inflammatory response of adipocytes in vitro. (A) Schematic diagram of cocultivation of 3T3-L1 cells and RAW264.7 cells. (B) Oil Red O staining of LDL-treated 3T3-L1 cells cocultured with NC-SCAP or OE-SCAP RAW264.7 cells (n = 3). Relative mRNA levels of inflammation cytokine (C), lipolysis (D), lipid synthesis (E), and lipid uptake (F) in LDL-treated 3T3-L1 cells cocultured with NC-SCAP or OE-SCAP RAW264.7 cells (n = 5). (G) Oil Red O staining of LDL-treated 3T3-L1 cells cocultured with Vec-SCAP or SCAPi-RAW264.7 cells (n = 3). Relative mRNA levels of inflammation cytokine (H), lipolysis (I), lipid synthesis (J), and lipid uptake (K) in LDL-treated 3T3-L1 cells cocultured with Vec-SCAP or SCAPi-RAW264.7 cells (n = 5). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 9 Expression levels of SCAP in macrophages also influences lipid homeostasis and inflammatory response of adipocytes in vitro. (A) Schematic diagram of cocultivation of 3T3-L1 cells and RAW264.7 cells. (B) Oil Red O staining of LDL-treated 3T3-L1 cells cocultured with NC-SCAP or OE-SCAP RAW264.7 cells (n = 3). Relative mRNA levels of inflammation cytokine (C), lipolysis (D), lipid synthesis (E), and lipid uptake (F) in LDL-treated 3T3-L1 cells cocultured with NC-SCAP or OE-SCAP RAW264.7 cells (n = 5). (G) Oil Red O staining of LDL-treated 3T3-L1 cells cocultured with Vec-SCAP or SCAPi-RAW264.7 cells (n = 3). Relative mRNA levels of inflammation cytokine (H), lipolysis (I), lipid synthesis (J), and lipid uptake (K) in LDL-treated 3T3-L1 cells cocultured with Vec-SCAP or SCAPi-RAW264.7 cells (n = 5). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 10 Expression levels of SCAP in macrophages also influences lipid homeostasis and inflammatory response of adipocytes in vitro. (A) Schematic diagram of cocultivation of HepG2 cells and THP-1 cells. (B) Oil Red O staining of LDL-treated HepG2 cells cocultured with NC-SCAP or OE-SCAP THP-1 cells (n = 3). Relative mRNA levels of inflammation cytokine (C), lipolysis (D), lipid synthesis (E), and lipid uptake (F) in LDL-treated HepG2 cells cocultured with NC-SCAP or OE-SCAP THP-1 cells (n = 5). (G) Oil Red O staining of LDL-treated HepG2 cells cocultured with Vec-SCAP or SCAPi-THP-1 cells (n = 3). Relative mRNA levels of inflammation cytokine (H), lipolysis (I), lipid synthesis (J), and lipid uptake (K) in LDL-treated HepG2 cells cocultured with Vec-SCAP or SCAPi-THP-1 cells (n = 5). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 10 Expression levels of SCAP in macrophages also influences lipid homeostasis and inflammatory response of adipocytes in vitro. (A) Schematic diagram of cocultivation of HepG2 cells and THP-1 cells. (B) Oil Red O staining of LDL-treated HepG2 cells cocultured with NC-SCAP or OE-SCAP THP-1 cells (n = 3). Relative mRNA levels of inflammation cytokine (C), lipolysis (D), lipid synthesis (E), and lipid uptake (F) in LDL-treated HepG2 cells cocultured with NC-SCAP or OE-SCAP THP-1 cells (n = 5). (G) Oil Red O staining of LDL-treated HepG2 cells cocultured with Vec-SCAP or SCAPi-THP-1 cells (n = 3). Relative mRNA levels of inflammation cytokine (H), lipolysis (I), lipid synthesis (J), and lipid uptake (K) in LDL-treated HepG2 cells cocultured with Vec-SCAP or SCAPi-THP-1 cells (n = 5). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 11 Macrophage SCAP deletion alleviates inflammatory response in liver tissue of PD-fed mice via inhibition of STING–NF-κB signaling. (A) Protein levels of P65 and P-P65 in total liver tissues, P65 in liver nuclear and cytosol (n = 6). (B) Protein levels of IKKα, IKKβ, P-IKKα/β, IκBα, and P-IκBα in liver tissues (n = 6). (C) Immunofluorescence staining of F4/80 and P65 in liver tissues (n = 3). (D) Schematic diagram of mechanisms by which STING activates NF-κB signaling. (E) Protein levels of STING, P-TBK1, and TBK1 in liver tissues (n = 6). (F) Immunohistochemical staining of STING in liver tissues (n = 6). (G) Immunofluorescence staining of F4/80 and STING in liver tissues (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 11 Macrophage SCAP deletion alleviates inflammatory response in liver tissue of PD-fed mice via inhibition of STING–NF-κB signaling. (A) Protein levels of P65 and P-P65 in total liver tissues, P65 in liver nuclear and cytosol (n = 6). (B) Protein levels of IKKα, IKKβ, P-IKKα/β, IκBα, and P-IκBα in liver tissues (n = 6). (C) Immunofluorescence staining of F4/80 and P65 in liver tissues (n = 3). (D) Schematic diagram of mechanisms by which STING activates NF-κB signaling. (E) Protein levels of STING, P-TBK1, and TBK1 in liver tissues (n = 6). (F) Immunohistochemical staining of STING in liver tissues (n = 6). (G) Immunofluorescence staining of F4/80 and STING in liver tissues (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 12 Macrophage SCAP deletion does not alter STING–NF-κB signaling in liver tissue of NCD-fed mice. (A) Protein levels of P65 and P-P65 in total liver tissues, P65 in liver nuclear and cytosol (n = 6). (B) Protein levels of IKKα, IKKβ, P-IKKα/β, IκBα, and P-IκBα in liver tissues (n = 6). (C) Immunofluorescence staining of F4/80 and P65 in liver tissues (n = 3). (D) Protein levels of STING, P-TBK1, and TBK1 in liver tissues (n = 6). (E) Immunohistochemical staining of STING in liver tissues (n = 6). (F) Immunofluorescence staining of F4/80 and STING in liver tissues (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 12 Macrophage SCAP deletion does not alter STING–NF-κB signaling in liver tissue of NCD-fed mice. (A) Protein levels of P65 and P-P65 in total liver tissues, P65 in liver nuclear and cytosol (n = 6). (B) Protein levels of IKKα, IKKβ, P-IKKα/β, IκBα, and P-IκBα in liver tissues (n = 6). (C) Immunofluorescence staining of F4/80 and P65 in liver tissues (n = 3). (D) Protein levels of STING, P-TBK1, and TBK1 in liver tissues (n = 6). (E) Immunohistochemical staining of STING in liver tissues (n = 6). (F) Immunofluorescence staining of F4/80 and STING in liver tissues (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 13 Macrophage SCAP deficiency inhibits expression of STING and P65 in eWAT of PD-fed mice. (A) Immunofluorescence staining of F4/80 and P65 in eWAT (n = 3). (B) Immunohistochemical staining of STING in eWAT (n = 6). (C) Immunofluorescence staining of F4/80 and STING in eWAT (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 13 Macrophage SCAP deficiency inhibits expression of STING and P65 in eWAT of PD-fed mice. (A) Immunofluorescence staining of F4/80 and P65 in eWAT (n = 3). (B) Immunohistochemical staining of STING in eWAT (n = 6). (C) Immunofluorescence staining of F4/80 and STING in eWAT (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 14 SCAP promotes inflammatory response through STING–NF-κB signaling activation in vitro. RAW264.7 macrophages were stimulated with LPS (300 ng mL−1) for 16 hours. (A) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in Vec-SCAP and SCAPi-RAW264.7 cells (n = 5). (B) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in NC-SCAP and OE-SCAP RAW264.7 cells (n = 5). (C) Protein levels of P-P65, P65, and SCAP in RAW264.7 cells (n = 3). (D) Protein levels of P65 in cytosolic and nuclear fractions (n = 3). Immunofluorescence staining of p65 nuclear translocation in SCAPi-RAW264.7 cells (E) and OE-SCAP RAW264.7 cells (F) (n = 3). (G) Protein levels of STING, P-TBK1, TBK1, IKKα, IKKβ, P-IKKα/β, IκBα, and P-IκBα in RAW264.7 cells (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 14 SCAP promotes inflammatory response through STING–NF-κB signaling activation in vitro. RAW264.7 macrophages were stimulated with LPS (300 ng mL−1) for 16 hours. (A) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in Vec-SCAP and SCAPi-RAW264.7 cells (n = 5). (B) Relative mRNA levels of IL1β, IL6, TNF-α, and MCP-1 in NC-SCAP and OE-SCAP RAW264.7 cells (n = 5). (C) Protein levels of P-P65, P65, and SCAP in RAW264.7 cells (n = 3). (D) Protein levels of P65 in cytosolic and nuclear fractions (n = 3). Immunofluorescence staining of p65 nuclear translocation in SCAPi-RAW264.7 cells (E) and OE-SCAP RAW264.7 cells (F) (n = 3). (G) Protein levels of STING, P-TBK1, TBK1, IKKα, IKKβ, P-IKKα/β, IκBα, and P-IκBα in RAW264.7 cells (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 15 SCAP recruits STING and TBK1 to the Golgi and activates NF-κB signaling. RAW264.7 macrophages were stimulated with LPS (300 ng ml−1) for 16 hours and 50 μmol/L 25-HC for 3 hours. (A) Schematic diagram of mechanisms by which macrophage SCAP activates STING–NF-κB. Immunofluorescence staining of STING and SCAP in liver tissues (B) or RAW264.7 cells (C). (D) Immunoblotting of immunoprecipitation with anti-SCAP, anti-TBK1, and anti-STING in OE-SCAP RAW264.7 cells. (n = 3). (E) Immunofluorescence staining of STING, TBK1, and Golgi 97 in RAW264.7 cells treated with LPS (n = 3). (F) Immunofluorescence staining of STING, TBK1, and Golgi 97 in RAW264.7 cells treated with LPS (n = 3). (G) Protein levels of P65 in cytosolic and nuclear fractions (n = 3). (H) Protein levels of TBK1, P-TBK1, P-P65, P65, and STING in RAW264.7 cells (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 15 SCAP recruits STING and TBK1 to the Golgi and activates NF-κB signaling. RAW264.7 macrophages were stimulated with LPS (300 ng ml−1) for 16 hours and 50 μmol/L 25-HC for 3 hours. (A) Schematic diagram of mechanisms by which macrophage SCAP activates STING–NF-κB. Immunofluorescence staining of STING and SCAP in liver tissues (B) or RAW264.7 cells (C). (D) Immunoblotting of immunoprecipitation with anti-SCAP, anti-TBK1, and anti-STING in OE-SCAP RAW264.7 cells. (n = 3). (E) Immunofluorescence staining of STING, TBK1, and Golgi 97 in RAW264.7 cells treated with LPS (n = 3). (F) Immunofluorescence staining of STING, TBK1, and Golgi 97 in RAW264.7 cells treated with LPS (n = 3). (G) Protein levels of P65 in cytosolic and nuclear fractions (n = 3). (H) Protein levels of TBK1, P-TBK1, P-P65, P65, and STING in RAW264.7 cells (n = 3). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central
Figure 16 Macrophage SCAP deletion ameliorates the degree of liver fibrosis in PD-fed mice. (A) Representative pictures of H&E staining and immunohistochemical staining of F4/80+ cells in mice fed a 16-week PD (n = 6). (B) Representative pictures of Sirius red staining and immunohistochemical staining of α-SMA in mice fed a 16-week PD (n = 6). (C) Levels of ALT and aspartate aminotransferase in plasma (n = 6). (D) Relative mRNA levels of fibrosis in liver tissues (n = 6). (E) Relative mRNA levels of inflammation cytokine in liver tissues (n = 6). (F) Protein levels of α-SMA, Col1a1, IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). (G) Protein levels of P-P65, P65, P-TBK1, TBK1, and STING in liver tissues (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).
Figure 16 Macrophage SCAP deletion ameliorates the degree of liver fibrosis in PD-fed mice. (A) Representative pictures of H&E staining and immunohistochemical staining of F4/80+ cells in mice fed a 16-week PD (n = 6). (B) Representative pictures of Sirius red staining and immunohistochemical staining of α-SMA in mice fed a 16-week PD (n = 6). (C) Levels of ALT and aspartate aminotransferase in plasma (n = 6). (D) Relative mRNA levels of fibrosis in liver tissues (n = 6). (E) Relative mRNA levels of inflammation cytokine in liver tissues (n = 6). (F) Protein levels of α-SMA, Col1a1, IL1β, IL6, TNF-α, and MCP-1 in liver tissues (n = 6). (G) Protein levels of P-P65, P65, P-TBK1, TBK1, and STING in liver tissues (n = 6). Data are expressed as mean ± SD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .0001; ns, nonsignificant (2-tailed unpaired t test in bar graphs).CC BY-NC-ND · PubMed Central

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Metadata

Authors
Huang, X., Yao, Y., Hou, X., Wei, L., Rao, Y., Su, Y., Zheng, G., Ruan, X. Z., Li, D., & Chen, Y.
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2022
Volume
14
Issue
1
Pages
1-26
ISSN
2352-345X
DOI
10.1016/j.jcmgh.2022.03.006
PMC
PMC9117819
Cited by
70
References
4
Language
en
Licence
Funders
  • Higher Education Discipline Innovation Project (D20028)
  • National Natural Science Foundation of China (81900406, 82170586)
  • China Postdoctoral Science Foundation (2019M663448)
  • Chongqing Medical University
  • Natural Science Foundation of Chongqing (CSTC2019JCYJ-BSHX0094)
  • Chongqing Research Program of Basic Research and Frontier Technology (cstc2020jcyj-zdxmX0007)

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